COPD, 11:591–602, 2014 ISSN: 1541-2555 print / 1541-2563 online Copyright © Informa Healthcare USA, Inc. DOI: 10.3109/15412555.2014.898035

REVIEW

Moving Towards Patient-Centered Medicine for COPD Management: Multidimensional Approaches versus Phenotype-Based Medicine—A Critical View Jose Luis Lopez-Campos1,2, Víctor Bustamante3, Xavier Muñoz2,4, Esther Barreiro2,5 1

Unidad Médico-quirúrgica de Enfermedades Respiratorias, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/ Universidad de Sevilla, Spain

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Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Madrid, Spain

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Servicio de Neumología. Hospital Universitario Basurto, Osakidetza. Departamento de Medicina, EHU-University of the Basque Country

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Pulmonology Service, Medicine Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain

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Pulmonology Department-Muscle Research and Respiratory System Unit (URMAR), Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)Hospital del Mar, Department of Experimental and Health Sciences (CEXS), Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona (PRBB), Barcelona, Spain

Abstract For decades, chronic obstructive pulmonary disease (COPD) has been considered a relentlessly progressive disease in which the deterioration of lung function is associated with an increase in symptoms, interrupted only by periods of exacerbation. However, this paradigm of COPD severity based on FEV1 has been challenged by currently available evidence. So far, three main approaches, though with contradictory aspects, have been proposed in order to address the complexity of COPD as well as to develop appropriate diagnostic, prognostic and therapeutic strategies for the disease: 1) the use of independent, clinically relevant variables, 2) the use of multidimensional indices, and 3) disease approaches based on clinical phenotypes. Multivariable systems seem superior to FEV1 in predicting prognosis and defining disease severity. However, selection of variables available from current literature must be confronted with issues of medical practice. Future evidence will be needed to reveal their effective relationship with disease longterm prognosis and to demonstrate the most adequate cutoff values to be used in clinical settings. Multidimensional scores provide a good prognostic instrument for the identification of patients with a particular degree of disease severity. Clinical phenotyping can help clinicians identify the patients who respond to specific pharmacological interventions; however, there is some controversy about the phenotypes to select and their long-term implications. Although these approaches are not perfect, they represent the first step towards patient-centered medicine for COPD. In the near-future, these different approaches should converge towards one new field to focus on the better management of COPD patients.

Introduction

Keywords: clinical phenotypes, COPD, guidelines, independent variables, multidimensional scores Correspondence to: Dr. Esther Barreiro, URMAR, IMIM-Hospital del Mar, PRBB, Dr. Aiguader, 88, E-08003 Barcelona, Spain, phone: +34 93 316 0385, fax: +34 93 316 0410, email: [email protected]

Traditionally, chronic obstructive pulmonary disease (COPD) has been considered a relentlessly progressive disease in which the deterioration of lung function is associated with an increase in symptoms, interrupted only by periods of exacerbation (1,2). This paradigm, which has been used to characterize COPD for decades, has recently been challenged by currently available evidence. First, not all patients with COPD experience FEV1 deterioration in a similar manner. In the recent study, Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE), Vestbo et al. evaluated the changes in FEV1 in a cohort of COPD patients over 3 years of follow-up (3). The analysis showed that there were large variations in the decline of FEV1 among the patients. Interestingly, the lung function of a group of the patients improved over the course of the study, challenging the idea that all COPD flow limitation is necessarily irreversible. 591

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Second, not all symptoms increase in a similar manner as FEV1 worsens. Although some patients experience more symptoms as FEV1 decreases, there are many patients who experience few symptoms at all levels of disease severity (4). Therefore, there is a poor correlation between symptom perception and FEV1 or FEV1-loss (4). In addition, recent studies suggest that the perception of symptoms may not be as stable as previously suggested. COPD-related symptoms are not consistently perceived by patients in the same way; changes in symptom perception have been observed over the course of a week or even within a single day (5,6), and several approaches have been developed to detect, measure, and manage the variations in the perception of symptoms among COPD patients (7,8). Finally, co-morbidities are important because they do not only affect the prognosis of the disease, but also modulate disease expression (9). Despite the fact that the inclusion of coexistent diseases can greatly increase the complexity of the clinical guidelines, a first attempt for an integrated approach to the disease was made recently (10). Moreover, discrepancies seen in COPD diagnosis and treatment observed in clinical practice, especially regarding the use of double bronchodilatation and/or inhaled corticosteroids (11–13), may be partly explained by the interplay between the presence of concomitant diseases other than COPD and factors such as lung functional assessment of the patients (11,14,15). Despite persisting controversies and difficulties in COPD diagnosis, the symptoms still play a key role in determining the best treatment. In this context, a kind of “mean-based medicine” − i.e., clinical decision making based on the achievement of a mean improvement for any given outcome in a clinical trial − is commonly used as a guide for drug choice. However, COPD patients vary considerably by their response to treatment because of a complex interplay of many factors. It follows that the assessment of COPD should be multidimensional from the moment of the diagnosis on. Several aspects of the clinical presentation of the disease, such as the perceived symptoms, the physical activity limitation, the lung function, and the number of exacerbations should be jointly evaluated in order to characterize the disease and to establish the optimal treatment approach. Although the benefits of a multidimensional approach seem clear, there is not one unique system to achieve this goal. As yet, three main approaches have been proposed to address the complexity of COPD and to develop an appropriate diagnostic and therapeutic strategy: 1) the use of several independent, clinically relevant variables, 2) the use of multidimensional indices, and 3) disease approaches based on clinical phenotypes. The three different approaches are reviewed in detail below. Moreover, the strengths and weaknesses of each strategy regarding its ability to predict the management of COPD patients in the near-future and usefulness to the clinicians are also being discussed. Although a systematic review for each method was outside the scope

of the current review, the referred literature represents that identified by a group of physicians and investigators who possess a strong clinical interest and knowledge in this specific area.

Independent Variables Description The first strategy to performing a multidimensional assessment of COPD involves the recognition of a group of independent prognostic variables related to the actual disease; taken together, these variables can provide a more comprehensive picture of the condition and help design a treatment strategy. In this approach, the selection of the variables that will be included in the treatment model is required. Many clinical, functional, morphological, and biological variables can be taken into account when establishing a treatment strategy and some areas of disease expression are shown in Table 1. Current evidence has generated more and more relevant variables, markers and measures related to the specific areas. For example, the COPD muscle dysfunction and weakness (16–19) has been studied extensively using biopsy specimens from the quadriceps muscle in which many different biological and cellular measurements have been obtained in the last few years (16,17). Table 1. Examples of clinical, anatomical, functional, and systemic characteristics with clinical and/or prognostic relevance in COPD Clinical features • Dyspnea • Mucous hypersecretion • Exercise capacity • Exacerbations Anatomic features and radiological evaluation • Airway thickness • Small airway involvement: bronchiectasis • Lung parenchyma involvement: emphysema distribution • Lung vessel involvement: pulmonary hypertension and pulmonary artery diameter Functional features • FEV1 decline • Hyperinflation • Bronchial reversibility • Bronchial hyperreactivity Respiratory inflammatory response • Local inflammatory load • Type of inflammatory infiltrates Systemic features and co-morbidities • Systemic inflammation • Nutritional alterations • Peripheral muscle dysfunction • Cardiovascular effects • Other co-morbidities

Copyright © 2014 Informa Healthcare USA, Inc

Patient-centered medicine for COPD

Figure 1. Skeletal muscle dysfunction is one of the most frequent systemic manifestations in COPD. Muscle wasting and atrophy worsen skeletal muscle dysfunction in patients with COPD. The properties of the muscles strength and endurance are impaired in COPD. Hence, exercise capacity and quality of life are limited in COPD patients.

Importantly, limb muscle dysfunction and weakness in COPD is also closely related to body composition as measured by fat-free mass (18), and represents a major contributing factor to poor exercise capacity and dyspnea, and quality of life in COPD patients (Figure 1) (18–20).

Selecting a set of variables can provide better mirror of the severity and the complexity of COPD. As it is important to establish a simple model to be applied in daily clinical practice, previous attempts have included a limited number of variables that are easily obtained, while also being sufficiently representative (21). A multidimensional evaluation of COPD patients is currently being conducted in Spain (22) to elucidate the relevance and implications of the candidate variables in the long run. The first initiative of this type was published in 2010 (23). In this original multidimensional approach to disease treatment (Figure 2), the author evaluated each of the different components of a three-dimensional scheme, based on FEV1, dyspnea and exacerbations. Each of the three axes was to be addressed independently and a joint strategy depending on which axis was most severely impaired in a particular patient was suggested (23). One year later, the GOLD 2011 document was based on the same idea (24,25). It presented the same three variables in the well-known 2 × 2 table in which the X-axis represents chronic symptoms (measured by the MRC dyspnea scale or the COPD assessment test (CAT) quality of life scale, the left Y-axis represents the FEV1 relative to predicted (FEV1 impairment), and the right

Figure 2. Schematic representation of the first initiative to establish a three-dimensional treatment strategy based on FEV1, dyspnea, and exacerbations. The figure has been reproduced with permission from Elsevier Spain, Health Science Division. www.copdjournal.com

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Y-axis represents the number of exacerbations. In the new 2013 GOLD strategy update, the Clinical COPD Questionnaire (CCQ) and the number of exacerbations (and hospitalizations) were included on the X-axis and the right Y-axis, respectively (26). Therefore, for each cell in the table a particular treatment is recommended.

Advantages and disadvantages Initially, it makes sense for a clinician to use several independent, clinically relevant variables with adequate threshold values to select a particular therapeutic strategy. Although many potential variables can be considered in such a scheme, the degree of obstruction, baseline dyspnea, and exacerbations are three clinical measures that are easily evaluable in daily clinical practice, which also have an impact on the patients’ perception of the disease in the short term (27). However, this philosophy of disease management is hampered by the intrinsic difficulty of adapting to individuals with a complex disease, and, despite its alleged simplicity, some controversies persist for its implementation in clinical settings as commented below. Limitations of the concept The main limitation is that Selecting a few clinically relevant patient-centered variables does not sufficiently capture the complexity of the disease. Thus, certain aspects of the disease that may impact the patient’s daily life or modulate the patient’s treatment may be missed (28). In this regard, aspects such as the presence of bronchiectasis or associated respiratory insufficiency, an eosinophilic inflammatory response, airway hyperresponsiveness, and the presence of chronic bronchitis may modulate disease expression, and these factors are clearly not included in a simple three-dimensional scheme (23,29). Thus, although a three-dimensional scheme may correctly describe the patients’ perceived health status, an adaptation beyond this general scheme is required for particular groups of patients with specific features of the disease. As a result, in the GOLD proposal, several treatment options were given for each cell in the 2 × 2 table because the disease is far more complex than what three dimensions can capture. Thus, simplicity is a major strength and a weakness of this approach. The balance between comprehensiveness and clinical utility is key for the implementation of this type of guideline. Limitations of the GOLD 2011 adaptation In the current review, the discussion about this multivariable evaluation proposal will be limited as a thorough assessment of the entire guideline is beyond the scope of the present review. The specific applicability of this multivariable conception as described in the GOLD strategy has raised several controversial issues. In this regard, the document is vague on the definition of risk and the type of risk intended to be reduced. A search for the term “risk” in the GOLD 2011 document refers

to the risk of adverse health-related events that may affect the patient at some point in the future (including the risk of exacerbations, the risk of disease progression, and the risk of future adverse events). Finally, the GOLD document states that “the assessment of exacerbation risk can also be seen as an assessment of the risk of poor outcomes in general,” suggesting that exacerbations are equally important as any other negative outcome. Nonetheless, this does not hold true for every patient. At this stage, it is important to remember the epidemiological concept of an ecological fallacy, i.e. an error in the interpretation of statistical data in which inferences about the nature of individuals are made from an inference about the group to which those individuals belong (30). In this context, although it may be true that the risk of exacerbations is related to the risk of poor outcomes in a cohort in general, this specific concept cannot be applied to a particular patient. Thus, the GOLD document requires further clarifications to specify the type of risks being under consideration. A second conflict observed in the GOLD version of the multivariable treatment approach is the use of different variables to define the same horizontal axis in the 2 × 2 table (26). Regardless of the threshold value arbitrarily chosen to differentiate less severe patients from highly symptomatic patients (which might be another topic for discussion), and although MRC and CAT scores can correlate with each other, the CAT and MRC scores do not necessarily match for a specific cohort or even in a particular patient. A few studies (31,32) have addressed the discrepancies found between the CAT and MRC scores. This example represents another ecological fallacy observed in the GOLD document. In the COPD Gene Study cohort, the category assignments made using the mMRC scale versus the St George’s Respiratory Questionnaire were not identical, nor were they even similar; there was significant heterogeneity depending on the scale used (31). Recently, a direct comparison between the MRC and CAT questionnaires showed that both questionnaires behaved quite similar to describe dyspnea at less advanced stages of the disorder, so that the cut-off points on the mMRC (≥1) and the CAT (≥10) were approximately equivalent in identifying low-symptom patients (32). However, there was a considerable discrepancy between the two scores, and the authors concluded that the GOLD assessment framework may require refinement (32). This discrepancy will most likely be greater or more complex when the CCQ is added to the equation in GOLD 2013. We understand that there is a need to evaluate chronic symptoms in COPD assessment and there is no perfect instrument for this purpose. However, in order to unify our language and COPD staging, a global initiative such as the GOLD strategy should better use one single measure, at least until this specific question is fully resolved. Third, the vertical axes of the 2 × 2 table also generate controversy, mainly because GOLD 2011 categorizes Copyright © 2014 Informa Healthcare USA, Inc

Patient-centered medicine for COPD patients in the upper portion of the 2 × 2 table for two reasons: exacerbations or FEV1 values (or both).The treatment strategy is the same regardless of which criterion a particular patient meets. However, it seems reasonable that the treatment for a patient whose problem is an impaired FEV1 should be different from the treatment for a patient who has a relatively preserved FEV1 score but experiences repeated exacerbations. Furthermore, once a patient is categorized in the upper portion of the table, the horizontal axis has very little importance because the treatment strategy for both C and D are identical in GOLD 2011, with a slight change in the 2013 update. In a recent analysis of the COPDGene Study the authors analyzed the reasons why patients were classified in the upper portion of the table and stratified 4484 patients according to the criteria they met (FEV1, exacerbations or both) to be allocated into the C or D subgroups (32). Interestingly, most of the patients classified as C and D met the FEV1 criteria alone, followed by exacerbations and the combination of both. This issue arises from trying to use a 2 × 2 table for three variables, since a 4 × 2 table would have been more convenient. Such a discrepancy will likely be greater when hospitalizations are added to the equation in GOLD 2013. The assignment of patients to GOLD categories and the distinctions between the cutoff points are based on large population studies that compare mean values. However, although these mean values represent the average behavior of a cohort, they do not represent the value for a specific subject. Thus, it is not possible to extrapolate the results to any particular case, resulting in another example of an ecological fallacy in the GOLD document. Fourth, the idea of a “frequent exacerbator” type of patient was mentioned in the ECLIPSE study (33). In this study (33), the frequent exacerbator phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient’s recall of previous treatment events. In fact, the single best predictor of exacerbations across all GOLD stages was the patient’s history of exacerbations (34). Twelve percent of the patients exhibited a persistent frequent exacerbator phenotype over the three years of the study, whereas 23% had had no exacerbations (34). It follows that 65% of patients in the ECLIPSE cohort showed a variable exacerbation rate. Thus, patients should be classified into the following categories depending on their exacerbation frequency: “no exacerbation”, “frequent exacerbator”, and “variable exacerbator”, a new type of patient not considered in the GOLD approach. The analysis of the long-term effects deserves specific attention. Since the publication of the GOLD 2011 update, several attempts have been made to analyze whether the new classification system was associated with survival. There have been two main publications to date. The first study (35), analyzed 6628 individuals from two similar population studies performed in an www.copdjournal.com

area of Copenhagen during an average period of 4.3 years. The authors found that the GOLD 2011 stratification performed well at identifying the individuals at risk of exacerbations. However, the patients in group B had significantly poorer survival than group C despite having a higher FEV1 level (35). In a second study (36), these findings were revisited in the COCOMICS study, a pooled data analysis from 11 different cohorts in Spain. Although the survival curves for B and C patients were very similar in the first years of the study, they separated in the third year of follow-up, confirming the findings of the study by Lange et al (35). Additional results were collected over 10 years of follow-up. However, although the new GOLD 2011 classification is a good prognostic marker, there were no differences between the old and new GOLD grading systems in their ability to predict mortality after one, three, or 10 years of follow-up (37). This finding opened a debate as to whether the new GOLD 2011 classification offered an improvement over a single FEV1 measurement. Nevertheless, we must keep in mind that GOLD 2011 was not conceived as a multidimensional prognostic measure, but as a new model to classify patients to best individualize their treatment. It is not surprising that the three variables together are good prognostic markers, given that each one of them individually is a good prognostic marker. Finally, the selection of different treatments for each type of patient is another source of controversy, but that is beyond the scope of the present review. In summary, multivariable systems seem adequate for disease management and symptom control, although controversy exists about their effect on the long-term prognosis of the disease compared with previous univariable models exclusively based on FEV1. There remains debatable, however, which are the best variables and the cut-off values that should be used to differentiate the types of patients. The idea behind this system seems to be valuable, but its scheme should be clearly improved.

Multidimensional Indices Description Instead of considering each variable independently, another possibility is to create a new variable composed of different independent variables, forming a so-called multidimensional index. Although a thorough review of all existing multidimensional systems is beyond the capabilities of the present review, an attempt to summarize a few of them has been made in the review. Briefly, the first multidimensional index was the BODE index (38). Each letter represents each one of the four components of the index: B for Body Mass Index, O for obstruction, D for dyspnea, and E for exercise. The BODE index was not only the first multidimensional index but also the one that has undergone greater clinical development. Several authors have studied its longitudinal association with outcomes, such as mortality or readmissions (39), the impact of changing one point in

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the index (40), and its relationship with exacerbations (41,42). Probably because of its wide diffusion, several authors have made new indices by modifying the original BODE index. The first attempt was to make a modified BODE (mBODE) by substituting the 6-minute walking test with peak oxygen uptake during a full cardiopulmonary exercise test (43). Although this index was validated longitudinally (44), the greater complexity of this measurement and its limited reproducibility (45) made it controversial. The second modification was to incorporate the number of exacerbations into the BODE index. Although initially evaluated as an additional variable for the index (eBODE), researchers decided to replace the six-minute walking test with the yearly number of exacerbations (BODEx) (46). Other BODE modifications included replacing the six-minute walking test with the incremental shuttle walking test (iBODE) (47), and altering the thresholds for the variables obtained from the data of another patient cohort (updated BODE; uBODE) (48). Multidimensional indices other than the BODE have also been developed. Among them is the SAFE index, which describes health-related quality of life as measured by the St. George’s Questionnaire, airflow limitations and exercise intolerance (49). The SAFE index was developed by a group in Malaysia and has demonstrated a moderate correlation with the number of exacerbations (49). The COPD Prognostic Index (CPI) (50) has demonstrated its capacity to predict exacerbations and hospitalizations. The DOSE (dyspnea, obstruction, smoking, and exacerbations) index was designed to be applied to individual patients as a reference for clinical management (51). The ADO (age, dyspnea, and obstruction) index showed prognostic capacity similar to the BODE index (48). Finally, the HADO (health, activity, dyspnea, and obstruction) index, with a variant that includes the patient’s age and hospitalizations (HADOAH) (52), was developed by a Spanish group and has similar prognostic capacity than other multidimensional indices.

Advantages and disadvantages As all of the multidimensional indices include a number of variables with prognostic importance, it is expected that they retain the prognostic capabilities of the individual variables when they are combined. In the pooled analysis of the COCOMICS study mentioned above (36), the authors found that the BODE and ADO indices were better predictors of long-term mortality after 6 months. However, none of the indices predicted well short-term mortality. Despite this evidence, none of the indices have been evaluated for their ability to select a particular treatment for a particular patient; moreover, these approaches may be prone to ecological fallacy, which may limit their use in clinical practice. So far, the most practical issue has been the selection of candidates for lung transplantation, which is cur-

rently based upon the BODE index (53). Nonetheless, the good prognostic value of these indices can be used to group patients with a particular degree of disease severity (54).

Clinical Phenotypes Description A phenotype is the composite of an individual’s observable characteristics or traits resulting from the expression of an individual’s genes as well as the influence of environmental factors and the interactions between the two. COPD is known to be a multigenic disease, and a large number of genes have been associated with the condition (55). As a result of the interaction between the genome and environmental factors (mainly, but not only, tobacco smoke), COPD occurs only in a particular group of subjects. Thus, COPD is a clear example of the result of gene-environment interactions. Similarly, once manifested, the different expressions of the disease also result from the interplay between genes and environmental factors. Thus, it is possible to say that COPD itself may also have different clinical expressions, the so-called clinical phenotypes. A clinical phenotype in COPD has been defined as “a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes” (56). The use of clinical phenotypes is a very recent approach that constitutes a step forward in the multidimensional evaluation of COPD. Instead of using different variables individually or jointly in a single index, clinical phenotyping evaluates groups of patients with several clinical features in common, establishing several well-recognized types of patients. If we carefully consider this definition, there are several clinical disease attributes of COPD (e.g. mucous hypersecretion, small airway involvement, FEV1 decline, etc.) that are related to clinically meaningful outcomes (e.g. survival, exacerbations, hospitalizations, etc.). In fact, it is likely that many, if not all, of the elements of the multidimensional approach listed in Table 1, and eventually others, could fit this definition. It follows that a reasonable approach must aim to obtain a balance between an exhaustive and a clinically applicable model. Investigators from Spain working in this specific field pioneered this new treatment approach. Moreover, the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) recently updated the COPD guidelines, while designing and publishing the Spanish COPD guidelines (GesEPOC) (57). GesEPOC was the result of a joint venture between SEPAR and other Spanish scientific societies actively working on the management of COPD patients (primary care, internal medicine, emergencies and patients’ associations). In addition, the guideline follows the Grading of Recommendations for Assessment, Development and Evaluation (GRADE) to ensure the quality of the evidence and Copyright © 2014 Informa Healthcare USA, Inc

Patient-centered medicine for COPD

Figure 3. Schematic representation of the clinical phenotypes in GesEPOC guidelines. The figure has been reproduced with permission from Elsevier Spain, Health Science Division.

the strengths of the recommendations (58). The establishment of GesEPOC is a step towards a new focus for COPD management, as it represents the first management approach based on clinical phenotypes (57). Very recently, guidelines from other countries also followed this initiative (59). Specifically, GesEPOC identifies four clinical phenotypes named A through D (Figure 3): the non-exacerbator (A), the mixed COPD/asthma phenotype (B), the exacerbator with emphysema (C), and the exacerbator with chronic bronchitis (D). In other words, GesEPOC maintains the two well-known phenotypes (chronic bronchitis and emphysema), adds the newly described mixed asthma/COPD phenotype, and considers a crosssectional phenotype (exacerbations) that modulates the other ones. Although a thorough description of each specific phenotype has already been published (60), a special comment regarding the mixed COPD/asthma phenotype may be needed herein (61). The coexistence of COPD and asthma has been a source of debate for decades (62). Until very recently, there were two opposing viewpoints in this debate. The British hypothesis proposes that asthma and COPD are distinct entities that are generated by distinct mechanisms (63). On the contrary, the Dutch hypothesis, formulated in the 60s, holds that the various forms of airway obstruction are different expressions of a single disease entity (64); this hypothesis created the idea of an association between these two diseases. The clinical reality is that there is overlap between the two conditions, and all physicians who care for chronic respiratory patients are aware of this reality. Notwithstanding, the debate about whether the co-occurrence of COPD and asthma should be considered a different clinical entity (65), a syndrome (66) or a clinical phenotype within one particular disease (67), is still ongoing. Clearly, there is a need to identify these patients by applying specific diagwww.copdjournal.com

nostic criteria to select proper therapeutic algorithms, as recently suggested (61). Within each phenotype, GesEPOC proposes the use of BODE quartiles to classify the disease severity in secondary care. Mixing phenotypes and BODE quartiles to determine the initial treatment results in a 4x4 table with 16 initial treatment possibilities (57). Nevertheless, once the patient has been assigned to a specific cell, the progression of treatment is based on exacerbations, FEV1, and symptoms (MRC, CAT). In primary care settings, where it is not possible to carry out the six-minute walking test, GesEPOC proposes using the BODEx index, while referring the patients to secondary care for a complete evaluation if the BODEx index is greater than five points.

Advantages and disadvantages The philosophy of this method is to identify clinical phenotypes that can help clinicians identify the patients who will respond to specific pharmacological interventions (68).The main advantage of this method is that it enables clinicians to easily recognize types of patients, who are clinically different from others, for whom a specific treatment strategy has been proven effective. In addition, an approach based on gene expression modulated by environmental factors seems to be the correct approach from a scientific point of view. However, several limitations of the concept itself and the GesEPOC guidelines must also be considered. Limitations of the concept There are three main limitations of the concept of phenotyping. First of all, a requirement of the phenotype evaluation is that the phenotypes must be collectively exhaustive and mutually exclusive. In other words, the phenotypes must differentiate patients with no overlap between them, and all patients must be represented

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by one phenotype. However, the complexity of COPD makes this condition very difficult to achieve, and thus, this concept has not been adjusted to the clinical reality of the disease. Second, if a clinical phenotype is considered as a feature of the disease, then the specific clinical presentation should be regarded as a natural manifestation of each particular case. Consequently, the presence of each phenotype should be invariably assessed regardless of the influence of treatment. However, therapies are specifically aimed to modify disease progression, thus making it difficult to assess the specific features of the condition once treatment has been started. Third, for the same reason, the presentation of the phenotypic feature should be stable over time and only modified by treatment. However, although some disease features (e.g., emphysema and bronchiectasis) may be stable over time others may change over time (e.g., exacerbations and hyperresponsiveness) on their own or in response to treatment. Perhaps the stability of these features should be incorporated into the accepted definition of the clinical phenotype (56). To make questions more complex, the variability of a specific feature can be a stable manifestation. For instance, the bronchodilator response is always present in some patients and is always absent in others, but in the vast majority of COPD patients, it is variable (69). The number of exacerbations is another example of a variable feature that has been discussed above (34).

GesEPOC adaptation The GesEPOC adaptation of the phenotype approach warrants several comments. Although a thorough review of the entire guideline is beyond the scope of the present manuscript, we will focus on the phenotype evaluation proposal. In that respect, we believe that there are at least four issues to be considered. First, as argued before, the selected phenotypes are not collectively exhaustive or mutually exclusive, and the exacerbator phenotype is not stable over time by definition. The authors, however, have acknowledged this limitation (57), and this approach will most likely be revised to include other phenotypes or to modify the diagnostic criteria in the near-future. Although the prognostic impact of chronic bronchitis and emphysema is well recognized, to our knowledge, studies aimed to simultaneously assess the prognostic significance of these phenotypes are not yet available. Second, several comments regarding the selected phenotypes are warranted. For instance, the mixed COPD/asthma phenotype was proposed on the basis of expert consensus (61). Thus, its validation should be performed prospectively. Although the majority of the criteria can be easily measured by clinicians, the need for the sputum eosinophilic counts makes it difficult to implement this approach on routine basis. The frequent exacerbator is a peculiar phenotype, and as explained above that the majority of patients with this phenotype

suffer from a variable number of exacerbations over the years (34). However, as a result of the need to establish stable phenotypes, the variable exacerbator patient seems to be a clinical reality not being considered in any guideline. Third, to facilitate the selection of the phenotype, GesEPOC proposes to study the phenotypes using a structured system that begins with identifying the exacerbator phenotype, as shown in Figure 4A. Nevertheless, an alternative proposal can be made in which the crossing of the lines in the algorithm is not projected as shown in Figure 4B. Fourth, the use of BODE may be complex and can also be influenced by ecological fallacy effects. According to GesEPOC, all patients should complete the six-minute walking test to establish their disease severity. It is not clear how often the BODE should be re-calculated and to what extent the treatment should be modified according to the new values. Furthermore, it seems that the BODE index should only be performed at the beginning of treatment. Then, once the patient is categorized into one of the 16 treatment possibilities, the progression of treatment is based on exacerbations, FEV1, and symptoms (MRC, CAT); thus, this approach ultimately has some similarities to the GOLD strategy. To sum up, GesEPOC is the first guideline based on phenotypes that seems adequate for disease management and symptom control, although there has been controversy over the phenotypes selected and the long-term implications. Eventually, the GesEPOC guideline also shares several common features with the GOLD strategy.

Global Vision and Conclusions It is clear that COPD is a complex multifaceted disease that requires a multidimensional evaluation to ensure the best possible treatment for each particular case. Different initiatives have been proposed, namely, multivariable strategies, multidimensional scores, and phenotype-based medicine. All of these strategies offer advantages and disadvantages, and the final model will have to be completed as the underlying science progresses in the near-future. An unresolved issue is the need to take into account the variability of disease presentation over time. Any algorithm that aims to become standard practice should take into account the fact that COPD is a variable disease and should also be versatile enough to let physicians adapt their treatment to the actual manifestations of the disease. For now, a delicate balance between comprehensive evaluation methods and tools that are feasible to be applied in clinical settings must be maintained. Our goal in COPD management and treatment will always have to be to modify the clinical manifestations of the disease and to limit its risks, whether using the GOLD strategy, a multidimensional grading system, or the clinical phenotype strategy. When using either the GOLD or the GesEPOC strategies, clinicians should aim to keep Copyright © 2014 Informa Healthcare USA, Inc

Patient-centered medicine for COPD

Figure 4. Schematic representation of the diagnostic algorithm of COPD clinical phenotypes. The figure has been reproduced with permission from Elsevier Spain, Health Science Division.

COPD patients in the type A category, with no exacerbations, very few symptoms, and a well-preserved lung function, at least as good as possible. While we are awaiting new developments, the approaches discussed herein represent the first steps towards patient-centered medicine for COPD care. In the future, as the knowledge of the disease progresses, underlying biological mechanisms, and new phenotypic and severity markers will be identified. The interrelationships between all aspects of the disease (e.g. genetic, biological, environmental, clinical, social) will surely offer new possibilities to converge towards a new focus on COPD management that aims at personalized treatment, challenging and overcomwww.copdjournal.com

ing the classical concepts of the disease (21,70). Before reaching this future, our effort must be to develop effective, but easy-to-apply clinical guidelines, without losing sight of every physician’s commitment which is the best care for the individual patient.

Acknowledgments The authors gratefully acknowledge Enzo Emanuele (Living Research s.a.s., Robbio, Italy) for his editorial assistance and MSc Ester Puig-Vilanova for her help with the references. This work has been supported by CIBERES; FIS 11/02029; FIS 12/02534; 2009-SGR-393; SEPAR 2010;

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FUCAP 2011; FUCAP 2012; and Marató TV3 (MTV307-1010) (Spain). Dr. Esther Barreiro was a recipient of the ERS COPD Research Award 2008.

Declaration of Interest Statement Dr. Jose Luis Lopez-Campos has received honoraria for lecturing, scientific advice, participation in clinical studies or writing for publications for (alphabetial order): Almirall, AstraZeneca, Bayer, Boehringer Ingelheim, Cantabria Pharma, Chiesi, Esteve, FAES, Ferrer, GlaxoSmithKline, Menarini, MSD, Novartis, Pfizer and Takeda (Nycomed). Dr. Víctor Bustamante, Dr. Xavier Munoz, and Dr. Esther Barreiro declares they have no conflict of interest, financial or otherwise in relation to this manuscript. The authors alone are responsible for the content and writing of the paper.

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